Quad Pill Matches Atripla, New Booster Cobicistat (GS 9350) Looks Good
with Atazanavir (Reyataz)
Gilead's "Quad" pill -- a coformulation containing
the experimental integrase inhibitor elvitegravir,
the novel boosting agent cobicistat (GS 9350), tenofovir,
-- was non-inferior to Atripla
(the efavirenz/tenofovir/emtricitabine combination pill) in
a head-to-head comparison of once-daily all-in-one regimens,
researchers reported at the 17th Conference on Retroviruses
& Opportunistic Infections (CROI 2010) this week in San
Francisco. A related study showed that cobicistat equaled
as a booster for atazanavir
Cohen from the Community Research Initiative of New England reported
on 2 studies involving cobicistat, which just received its generic name.
agents (pharmacoenhancers) interfere with liver enzymes that process
other drugs, thereby raising the latter drug's blood concentration.
reported, cobicistat has demonstrated good boosting activity in
combination with atazanavir and elvitegravir.
Quad vs Atripla
first trial, Study 236-0104, a total of 71 treatment-naive participants
were randomly assigned (2:1) to take the Quad pill or Atripla once-daily
for 48 weeks.
(about 90%) were men, the average age was about 35 years, and about
75% were white. All had a baseline viral load of >5000 copies/mL
and no resistance to the 3 earliest antiretroviral drug classes. The
average viral load was about 40,000 copies/mL and the mean CD4 cell
count was approximately 400 cells/mm3.
of participants in the Quad arm and 13% in the Atripla arm discontinued
24 weeks, 90% of participants in the Quad group achieved viral load
< 50 copies/mL, compared with 83% in the Atripla group, in an
intent-to-treat (ITT) analysis with missing patients counted as
result showed that the Quad pill was non-inferior to Atripla, though
the study was not designed as a non-inferiority trial.
a second ITT analysis with missing patients excluded, 96% in the
Quad group and 95% in the Atripla group achieved HIV RNA < 50
CD4 count increases at week 24 were about equal, 123 cells/mm3 in
the Quad arm and 124 cells/mm3 in the Atripla arm.
patients in the Quad arm experienced drug-related adverse events
of any severity, compared with 57% in the Atripla arm, largely attributable
to fewer efavirenz-associated central nervous system (CNS) side
participants in the Quad arm and 1 in the Atripla discontinued early
due to adverse events.
receiving cobicistat showed a greater -- though still small -- increase
in serum creatinine (a marker of potential kidney impairment), +0.14
mg/dL versus +0.04 mg/dL in the Atripla arm.
estimated glomerular filtration rate (eGFR, a calculation of kidney
function) was lower (i.e., worse) in the Quad arm at 24 weeks, 111
vs 126 mL/min.
findings led the investigators to conclude that the Quad pill "met
criteria for non-inferiority" to Atripla, with "fewer study
drug-related adverse events (particularly CNS)."
positive efficacy and safety results indicate that the Quad has the
potential to become an important new treatment option in HIV therapy,"
Cohen said in a press release issued by Gilead Sciences.
At the opening press conference, CROI co-chair John Mellors highlighted
once-daily complete regimen combination pills like Atripla and the Quad
pill as the future of HIV therapy. Ideally, he said, there will be an
"armamentarium" of all-in-one regimens with no overlapping
components, meaning no risk of cross-resistance when patients switch
from first-line to second-line regimens.
second trial, Study 216-0105, a total of 79 previously untreated patients
were randomly assigned (again 2:1) to receive 150 mg cobicistat or 100
mg ritonavir, all with once-daily atazanavir
plus tenofovir/emtricitabine (Truvada), for 48 weeks. Participant
characteristics were similar to those in the previous study, but this
group had a higher proportion of non-white patients.
of participants in the cobicistat arm and 10% in the ritonavir group
2 drugs produced statistically similar virological suppression rates.
week 24, in an ITT missing=failure analysis, 84% of participants
in the cobicistat arm achieved HIV RNA < 50 copies/mL, compared
with 86% in the ritonavir arm.
an ITT missing=excluded analysis, the corresponding rates were 91%
in the cobicistat arm versus 96% in the ritonavir arm.
taking cobicistat experienced a median CD4 cell gain of 206 cells/mm3
compared with 190 cells/mm in the ritonavir arm.
of drug-related adverse events were similar overall, at 20% in the
cobicistat arm versus 24% in the ritonavir group (although >
80% in both arms had elevated bilirubin associated with atazanavir).
people in the cobicistat arm and 1 in the ritonavir arm discontinued
early due to adverse events.
serum creatinine increased more in patients taking cobicistat, +0.18
mg/dL compared with +0.14 mg/dL in the ritonavir arm.
eGFR was again lower among cobicistat recipients, 102 vs 111 mL/min.
concluded that cobicistat and ritonavir had similar efficacy, safety,
concern in these studies was the signal of kidney toxicity suggested
by elevated elevated serum creatinine and reduced eGFR in people taking
cobicistat. Creatinine is one of the factors used to compute eGFR. In
discussing the findings, Cohen explained that cobicistat alters estimated
but not actual GFR.
studies of healthy HIV negative volunteers suggested cobicistat may
inhibit kidney tubular secretion -- leading to elevated creatinine --
but does not seem to cause the type of nephrotoxicity seen with other
drugs. Nevertheless, caution may be warranted with a pill that combines
cobicistat and tenofovir, which has been linked to kidney impairment.
on the favorable results from these studies, Gilead announced that large-scale
Phase 3 studies of the Quad pill and cobicistat are expected to start
by the middle of 2010.
Community Research Initiative of New England, Boston, MA; Whitman Walker
Clinic, Washington, DC; Orlando Immunology Center, Orlando, FL; Gilead
Sciences, Foster City, CA.
Cohen, D Shamblaw, P Ruane, and others. The single-tablet, fixed-dose
regimen of elvitegravir/GS-9350/emtricitabine/tenofovir DF (Quad) achieves
a high rate of virologic suppression and GS-9350 is an effective booster.
17th Conference on Retroviruses & Opportunistic Infections (CROI
2010). San Francisco. February 16-19, 2010. Abstract 58LB.
Sciences. Gilead's Single-tablet "Quad" Regimen for HIV Achieves
a High Rate of Virologic Suppression in Phase II study. Press release.
February 17, 2010.